Degradable haemostat composition

ABSTRACT

In one aspect, the present invention includes a haemostat composition that has been washed with an alkali solution to reduce the presence of endotoxins, and which is able to safely gradually and fully degrade in a human or animal body within about 30 days and so can be utilised by physicians to stem a flow of blood and promote healing both after as well as during surgical procedures.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is the U.S. national phase entry of PCT/GB2014/051624,with an international filing date of May 28, 2014, which claims priorityto and the benefit of GB 1309674.8, filed on May 30, 2013, the contentsof which are hereby incorporated by reference in their entirety.

TECHNICAL FIELD

The present invention relates to a haemostat composition that is capableof safely gradually and completely degrading within the body of a humanor animal, and can therefore be utilised by physicians to stem a flow ofblood and promote healing both after as well as during surgicalprocedures.

BACKGROUND

Haemostat materials for use in the treatment of wounds or other openingsat a physiological target site in or on human or animal body which areexuding blood and/or other bodily fluids have been known for some time.These haemostat materials act to absorb the blood and/or other bodilyfluids, and also stem the flow of them from the body. Haemostatmaterials for such use are described in, for example, WO 2009/130485 andWO 2012/123728 to MedTrade Products Ltd., and are commercially availableunder the trade name Celox®.

One material that is commonly employed as a haemostat material ischitosan. Chitosan is a known haemostat material, and is a derivative ofsolid waste from shellfish processing and can be extracted from fungusculture. It is a cationic polymeric material that is insoluble in water.

There are many different types of chitosan that may be used as ahaemostat material, with different haemostatic properties. The differenttypes of chitosan may have different molecular weights, differentdegrees of deacetylation, different arrangements of the two monomers,different chiral forms, or they may be derived from different species orsources (and fungi), or may have been treated differently duringmanufacture. Each of these differences can impact upon the levels ofsolubility and polymer structures of the respective chitosan materials,and therefore provide different chitosan materials having differinghaemostatic properties.

The control of bleeding is essential and critical during surgicalprocedures. The aim of controlling bleeding is essentially to minimizeblood loss, which in turn may shorten the duration of the surgery in theoperating room and ultimately lead to a reduction in post-surgicalcomplications. Haemostat compositions are of significant use duringsurgery for this purpose, but must always be removed at the end of theprocedure when the incision in the patient is closed up.

However, there remains a need for a haemostat composition that is ableto be used safely within the human or animal body, after as well asduring surgical procedures, and which can subsequently be allowed toremain in the body to promote healing post-surgery. It would bebeneficial to have a haemostat composition that is safely absorbablewithin the body within a defined period of time, as this would eliminatethe need to remove the product prior to closure of the patient, andwould allow the haemostat composition to remain in the body to reducethe likelihood for re-bleeding post-surgery. Further, such an absorbableand degradable haemostat composition would negate the need for furthersurgery to remove the haemostat. Such a degradable haemostat compositionfor post-surgical use has never previously been developed.

SUMMARY

Therefore, in accordance with the invention, there is provided ahaemostat composition comprising a chitosan, chitosan salt or chitosanderivative, wherein the haemostat composition is in non-fibrous form,and is able to fully degrade in a human or animal body within about 30days.

By “haemostat”, it is meant herein any agent which is capable ofproducing a clot or plug which stops or reduces bleeding when it comesinto contact with blood or other bodily fluid.

By the term ‘chitosan derivative’ is meant herein a partiallydeacetylated chitin, which may have different percentages ofdeacetylation, as desired. Typically, the partially deacetylated chitinsuitable for use in the present invention has a deacetylation degreeabove about 50%, more typically above about 75% and most typically aboveabout 85%.

Also herein included within the term ‘chitosan derivative’ are reactionproducts of chitosan with other compounds. Such reaction productsinclude, but are not limited to, carboxy methyl chitosan, hydroxyl butylchitin, N-acyl chitosan, O-acyl chitosan, N-alkyl chitosan, O-alkylchitosan, N-alkylidene chitosan, O-sulfonyl chitosan, sulfated chitosan,phosphorylated chitosan, nitrated chitosan, alkalichitin,alkalichitosan, or metal chelates with chitosan, etc.

Suitable non-fibrous forms for the haemostat composition of theinvention include, but are not limited to, granules, powder, a sheet, afoam, a freeze dried foam, a compressed foam, a film, a perforated film,beads, a gel, a hydrogel (sheets and amorphous), or a laminate, or acombination of any two or more thereof.

By ‘sheet’ is meant an aqueous form of the chitosan, chitosan salt orchitosan derivative that has been dried into a sheet of aphysiologically acceptable degradable material.

The haemostat composition of the invention will typically be completelydegraded within the human or animal body between about 1 to no more thanabout 30 days after its introduction into the body, more typicallywithin this range after about 4 days, still more typically within thisrange after about 7 or about 10 days. As the haemostat composition willtypically not be completely degraded within about 24 hours, moretypically not within about 4 days, or even within about 7 days, thispermits the haemostat composition to remain in the human or animal bodyfor a sufficient period of time after the surgical procedure or closingof a wound, so that it may aid in preventing or reducing any incidenceof re-bleeding at the physiological target site, and also aid in thehealing process. Too rapid a degradation could potentially lead to latere-bleeds and would limit the effectiveness of the haemostat compositionin aiding in the post-surgery healing process. For example, thehaemostat composition may be still be present in the body about 7 daysafter the surgical procedure or closing of a wound, but will havesubsequently completely degraded after 30 days.

The haemostat composition of the invention will typically also contain aphysiologically acceptable acid. The amount of acid relative to thechitosan, chitosan salt or chitosan derivative has an effect on thedegradation properties of the haemostat composition of the invention.Typically, if the amount of acid in the haemostat composition is atabout 20% or less by weight of the haemostat composition, such as in WO2009/130485 to MedTrade Products Ltd, the degradation time is greaterthan 30 days. A degradation period above 30 days would mean that theproduct of the invention would fall into a different medical regulatoryand safety category. Conversely, if the ratio of acid is greater thanabout 70% by weight of the haemostat composition, the haemostatcomposition typically dissolves too rapidly upon contact with blood,loses its gelling properties, and because it degrades too quickly, italso loses its ability to be an effective haemostat.

The chitosan, chitosan salt or a chitosan derivative used in the presentinvention does not need to be subjected to any heat treatment, otherthan optionally in the removal of any solvents to dry the composition,which is typically done at temperatures of no more than 40° C. No heattreatment is necessary after the composition has been dried. This isbecause subjecting the composition to heat treatment would impartundesirable increased insolubility and cohesion properties upon thehaemostat composition, which would result in the haemostat compositionhaving reduced degradation properties, leading to it being unable todegrade sufficiently in the body within 30 days.

According to another embodiment of the invention, the haemostatcomposition will typically have an absorption of less than about 20 g/g,more typically less than about 15 g/g. By an absorption of less thanabout 20 g/g is meant that the haemostat composition will absorb lessthan 20 g of fluid per gram of the composition, typically about 15-18g/g.

The haemostat composition of the invention works effectively at normalbody temperatures (37° C.).

According to one embodiment of the invention, the haemostat compositionmay be blended with other physiologically safe materials, such as, forexample, oxidised cellulose or collagen, etc. Other suitable and safelydegradable materials that may be combined with the haemostat compositionwill be apparent to the person skilled in the art.

According to one embodiment of the invention, the haemostat compositionconsists of a chitosan, chitosan salt or chitosan derivative togetherwith a physiologically acceptable acid. In this embodiment, no carriermaterial is used for the composition.

The physiologically acceptable acid is typically present in an amount ofmore than about 20% and below about 70% by weight of the haemostatcomposition, more typically more than about 25% by weight of thehaemostat composition to about 65%, more typically from about 30% toabout 60% by weight of the haemostat composition, more typically fromabout 35% to about 55% by weight of the haemostat composition. However,amounts of acid of about 35%, 40%, 45%, and 50% are also envisagedwithin the scope of the invention.

For example, if chitosan is in the form of granules, then an amount ofacid, such as lactic acid, between about 45-65% by weight of thehaemostat composition, more typically between about 50-60% by weight ofthe haemostat composition may be used, most typically between about53-57% by weight of the haemostat composition. It will be appreciatedthat the optimum amount of acid for the desired degradation propertiesmay vary with different acids, and also with different grades ofchitosan. The optimum amount of acid required for the desireddegradation properties may differ depending upon the form of thechitosan haemostat, among other factors.

It will be appreciated that the optimum amount of acid for a desiredrate of degradation may vary with different carboxylic acids, withdifferent amounts of the acid, and also with the different grades andtypes of chitosan detailed above.

Examples of acids that may be used include, but are not limited to,organic acids and/or inorganic acids, including carboxylic acids,monovalent, divalent or multivalent acids. Non-limiting examples ofcarboxylic acids include formic acid, acetic acid, ascorbic acid,halogen acetic acids (such as fluoro- or chloroacetic acid), propanoicacid, propenoic acid, lactic acid, succinic acid, acrylic acid,glyoxylic acid, pyruvic acid or a hydroxy propionic/butanoic acid, orcombinations of any two or more thereof. More typically, the carboxylicacids used are one or more acids selected from lactic, acetic andsuccinic acids. Most typically, the carboxylic acid used compriseslactic and/or acetic acids, especially lactic acid. Non-limitingexamples of inorganic acids include one or more selected fromhydrochloric acid and sulphuric acid. The use of an acid which isalready present in the human or animal body is advantageous infacilitating the bioacceptability of the haemostat composition as itdegrades.

As discussed above, the amount of acid that is present in the haemostatcomposition can significantly impact upon the degradation properties ofthe composition, and may also be determined by the form of thecomposition that is to be used.

According to another embodiment of the invention, the haemostatcomposition comprises a chitosan salt and the physiologically acceptableacid is a carboxylic acid, such as lactic acid, while the haemostatcomposition is in the form of granules or powder.

According to another embodiment of the invention, the haemostatcomposition comprises a chitosan salt, the physiologically acceptableacid is a carboxylic acid, such as lactic acid, and the acid is presentin an amount of between about 45-60% by weight of the haemostatcomposition, more typically between about 50-55% by weight of thehaemostat composition, and the haemostat composition is in the form ofgranules or powder.

According to one embodiment of the invention, the haemostat compositionis a chitosan salt. If a chitosan salt is used, the salt is typicallyprepared in situ when the chitosan comes into contact with anappropriate acid. It will be appreciated that the acid may be anyinorganic or organic acid which yields a chitosan salt that is solublein bodily fluids and that can be safely degraded within the human oranimal body. The appropriate acids or combination of acids for yieldinga soluble chitosan salt will be apparent to a skilled person. Forexample, chitosan phosphate is substantially insoluble in water, and souse of phosphoric acid alone would hence be less suitable as the acidfor this purpose. Typical chitosan salts include herein, but are notlimited to, one or more salts selected from chitosan acetate, chitosanlactate, chitosan succinate, chitosan malate, chitosan acrylate,chitosan formate, chitosan ascorbate, chitosan fluoroacetate, chitosanchloroacetate, chitosan propanoate, chitosan glyoxylate, chitosanpyruvate, chitosan sulphate, or chitosan chloride. More typically, thechitosan salt used in the present invention is chitosan lactate.

Chitosan can act as a haemostat in two ways; either by gelling withwater in the blood and bonding to wet tissue to plug a wound, or bydissolving and bonding with the surface of red blood cells to create aclot-like gel. The properties of the combinations of chitosan and acidare dependent upon the precise nature of the chitosan (e.g. molecularweight and degree of deacetylation), as well as the particular acid usedand the quantities present.

Chitosan salts are ideally suited for the applications described hereinas chitosan is readily broken down in the body. Chitosan is converted toglucosamine by the enzyme lysozyme and is therefore excreted from thebody naturally. It is not necessary to take any measures to remove thechitosan from the body.

Furthermore, chitosan salts exhibit mild antibacterial properties and assuch their use reduces the risk of infection.

Typically, the molecular weight of the chitosan used for the preparationof the haemostat composition according to the present invention is lessthan about 2,000,000, more typically less than about 1,000,000, and evenmore typically less than about 500,000, and most typically less thanabout 175,000.

The viscosity of the chitosan used according to the invention maytypically be less than about 1000 cps, more typically less than about500, even more typically less than about 300. Advantageously, theviscosity is from about 40 to about 200 cps when measured on aBrookfield viscometer at 20° C.

The chitosan typically has a pH of from about 6.0 to about 8.0. Chitosansalts can have a pH from about 3.5 to about 8.0. The pH is largelydependent upon the particular chitosan or chitosan salt used, as theyeach have a different pH.

The chitosan material may be provided in a sterile or non-sterile form.Where the material is initially provided in a non-sterile form,sterilisation may be carried out using any of the known methods, such asgamma irradiation, electron beam treatment, heat treatment, etc, or bytreatment using ethylene oxide. A material in a non-sterile four may beprovided in combination with one or more preservatives. However, for agreater ease of use for a physician, it is preferred that the haemostatcomposition is provided in a pre-sterilised form.

According to one embodiment, if the haemostat is in particulate orgranular form, at least about 50% of the particles or granules have anaverage particle size of greater than about 250 microns (60 mesh), whileabout 20% to about 30% of the particles have an average particle size ofless than about 250 microns. Typically, almost all of the particles,such as about 99% thereof, have an average particle size of less thanabout 2000 microns (10 mesh), with less than about 1%—and ideally0%—having an average particle size greater than about 2000 microns.Also, about 5% of the particles have an average particle size greaterthan about 1000 microns. By ‘particle size’ is meant herein the size ofa granule between its furthest points, and the ‘average particle size’represents the average of all of the particle sizes in a batch ofgranules in the haemostat composition.

If the haemostat composition is in the form of a sheet or film, then itmay take any suitable form and may be provided in a range of differentsizes, shapes and thicknesses necessary to deal with a physiologicaltarget site, such as square, rectangular, circular or elliptical. Thephysiological target sites to be treated may be of differing sizes andshapes. For example, the sheet or film may be a generally flat shapewith little height relative to its width/depth. Any regular or irregularshape may be employed. It may also be provided in larger dimensionswhich can then be cut to the required size.

The thickness of the sheet or film may be varied between upper and lowerlimits as desired. The upper limit of the thickness is typically about 5cm, down to a few microns, such as 5-10 microns. It is however importantthat the sheet or film is flexible so that it can be curved to fit thecontours of the physiological target sites to be treated, if necessary.Typically, the thickness is from about 1.5 mm to about 3.0 mm.

In accordance with the invention, it is possible to control the rate ofdegradation of the haemostat composition by selecting particularcombinations of chitosan properties, such as molecular weight orviscosity, or selecting a particular chitosan salt, as well as byvarying the amount of acid component.

Of course, in order that the haemostat composition of the invention isable to be safely inserted into the human or animal body, it must beentirely physiologically acceptable, and only contain components thatare not harmful to the human or animal body.

The physiological target site may be any site in the body of an animalthat is exposed during a surgical procedure. The animal may be a humanor a non-human animal.

The haemostatic composition described herein provides and maintainseffective haemostasis when applied to a wound requiring haemostasis.Effective haemostasis, as used herein, is the ability to control and/orabate capillary, venous, or arteriole bleeding within an effective time,as recognized by those skilled in the art of haemostasis.

In certain embodiments, the haemostatic composition of the presentinvention is effective in providing and maintaining haemostasis in casesof severe or brisk bleeding. As used herein, severe bleeding is meant toinclude those cases of bleeding where a relatively high volume of bloodis lost at a relatively high rate. Examples of severe bleeding include,without limitation, bleeding due to arterial puncture, liver resection,blunt liver trauma, blunt spleen trauma, aortic aneurysm, bleeding frompatients with over-anticoagulation, or bleeding from patients withcoagulopathies, such as haemophilia.

The haemostatic composition herein also provides and maintains effectivehaemostasis when applied to a wound whereby the patient and/or personrequiring haemostasis are on anti-coagulant therapy, for example,heparin and warfarin.

In surgical procedures whereby haemostasis may be critical to survivalof the patient, it is therefore desirable to have a haemostaticcomposition that does not require preparation and that is ready for useupon removal from its packaging. The haemostatic composition of theinvention fulfils this requirement. Also, the haemostatic composition ofthe invention is capable of being applied on either surface thereof,reducing the risk of incorrect application.

It is also beneficial to deliver a haemostat composition that is able toadhere to the body tissues, ensuring that any haemostat product is notremoved due to movement and stays in place until it is fully absorbed bythe body, reducing the risk of re-bleeding. The haemostatic compositionof the invention has a known metabolic pathway, via the known conversionof chitosan to glucosamine by the lysozyme, so the body can dispose ofit in a safe manner.

Further components which may be added to the haemostat compositioninclude, but are not limited to, one or more selected frompharmaceutical agents; wetting agents such as surfactants; growthfactors; cytokines; agents which absorb agents which delay healing suchas MMP's (matrix metalloproteinases) and elastase; and/or anotherhaemostat component, such as calcium, vitamin K, fibrinogen, thrombin,factor VII, factor VIII, clays such as kaolin, oxidised regeneratedcellulose, gelatin, or collagen, etc.

Typical levels of any of these components could be from about 50 ppmlevels up to about 50% by weight of the haemostat composition. Moretypical levels would be less than about 10%, still more typically lessthan about 5%, by weight of the haemostat composition. Less than about1% by weight of the haemostat composition of these components is alsoenvisaged within the invention.

In order to evaluate the degradation properties of the haemostatcomposition, the composition has been tested in solutions which closelyreplicate the conditions within the human or animal body in which itwould be used. As such, the haemostat composition of the invention hasbeen shown to degrade in lysozyme solution, serum and simulated woundfluid. The simulated wound fluid contains 50% Fetal Bovine Serum and 50%Peptone water (0.9% NaCl+0.1% peptone in de-ionised H₂O).

Firstly, the haemostat composition of the invention is immersed in asolution of each of lysozyme solution, serum and simulated wound fluid.In each case, the volume of the solution is greater than maximumabsorbency of the composition.

The haemostat composition and the solution is then sealed and incubatedat 37° C.—i.e. body temperature—for a period of up to 30 days.

During this period, the degradation of the composition is visuallyassessed at numerous time points to determine whether the compositionhas completely degraded.

According to a further aspect of the invention, there is provided amethod of manufacturing a haemostat composition comprising a chitosan,chitosan salt or chitosan derivative, wherein the haemostat compositionis in a non-fibrous form, and is able to fully degrade in a human oranimal body within about 30 days. The method may comprise coating thechitosan, chitosan salt or chitosan derivative with a physiologicallyacceptable acid.

The acid used may be any of those listed herein above, and in any of theamounts as detailed above. The acid is typically lactic acid, but is notlimited thereto. Once the chitosan, chitosan salt or chitosan derivativehas been coated by the acid, it is dried.

In one embodiment, the chitosan raw material may first be washed toreduce the presence of endotoxins prior to the coating step. This may becarried out using contacting the chitosan, chitosan salt or chitosanderivative with an alkali solution to form a mixture, and then leavingthe mixture for a period of time, which may be as short as about 1minute to longer than about 12 hours, before finally drying the mixture.By ‘alkali solution’ is meant a solution having a pH value of greaterthan pH 7.5.

The concentration of alkali solution used in the process may be fromabout 0.01M to about 1M. Typically, the concentration of alkali solutionis from about 0.02M to about 0.2M, more typically about 0.1M.

The quantity of alkali solution to chitosan may be in the range of fromabout 1 part chitosan to about 10 parts alkali solution up to about 10parts chitosan to about 1 part alkali solution. Typically, the quantityof alkali solution to chitosan is about 1 part alkali solution to about2 parts chitosan, more typically about 1 part alkali solution to about 1part chitosan.

The alkali solution may comprise an alkali or alkaline earth componentselected from the following, either alone or in combination: metalhydroxides, metal carbonates, metal bisulphites, metal persilicates,conjugate bases and ammonium hydroxide.

Suitable metals include sodium, potassium, calcium, or magnesium.Typically, the alkali component is sodium hydroxide, potassium hydroxideor sodium carbonate. Typically, sodium hydroxide is used.

Additionally, the haemostat composition of the invention may be firstwashed to reduce the presence of endotoxins as described above.Typically, this washing step is carried out.

Subsequently, the chitosan, chitosan salt or chitosan derivative is thenprocessed to form the final product. By way of a typical butnon-limiting example where the haemostat composition according to theinvention is in granular or powder form, granules are washed with thealkali solution and dried. The physiologically acceptable acid is thenapplied to the washed granules, which are dried and then milled toparticles having the desired average particle size, which are thenpresented in applicators or pouches. Alternatively, where the haemostatcomposition is in the form of e.g. a sheet or film, once the sheet orfilm has had the physiologically acceptable acid applied to it, it isthen dried, before finally being cut into pieces of the desired sizes.

In each embodiment, the haemostat composition is typically alsosterilised prior to being packaged, in order that a physician can usethe composition directly from its packaging.

The present invention also provides a method of absorbing a discharge ofa fluid, such as blood, and a method of stemming a flow of a fluid suchas blood from a physiological target site, comprising applying to thetarget site a haemostat composition as described herein.

According to a further aspect of the invention, there is provided a useof a haemostat composition as described herein in absorbing a dischargeof a bodily fluid from a physiological target site, or of stemming aflow of a fluid discharged from a physiological target site.

When the haemostat composition of the invention is used in absorbing adischarge of a fluid, or in stemming a flow of a fluid such as bloodfrom a physiological target site, it is typically retained within ahuman or animal body after a medical procedure in order to providepost-surgical haemostasis, to reduce the likelihood for re-bleedingpost-surgery and to promote post-surgical healing.

DETAILED DESCRIPTION

The invention will now be described further by way of example withreference to the following examples which are intended to beillustrative only and in no way limiting upon the scope of theinvention.

EXAMPLES Method

The total absorbency of the haemostat composition of the invention isdetermined using simulated wound fluid, serum and lysozyme solution.This is undertaken by determining the maximum absorbency of thematerials by slowly adding fluid to the materials until no more can beabsorbed. The amount of fluid absorbed is calculated from the wet weightminus the dry weight.

Using the total absorbency volume for the material to be tested, thisvolume of lysozyme solution, simulated wound fluid or serum is decantedinto a clean sealable beaker.

The haemostat composition is added into the solution (the solutionvolume being greater than the maximum absorbency of the haemostatcomposition), ensuring that the weight of product is not greater thanthe absorbency potential for the volume of fluid within the beaker.

The haemostat composition and solution are sealed and incubated at 37°C. (i.e. body temperature) for up to 30 days.

At each time point the solution is visually assessed to determinewhether and to what degree the haemostat composition has degraded.

It is to be noted that at maximum absorbency at day 1, the degradationtime is quicker than if the same volume of solution is applied graduallyover a 5 day period.

The haemostat composition is considered to have completely degraded ifthe viscosity of the lysozyme solution, simulated wound fluid or serumfalls below 10 cps as measured at 20° C. on a Brookfield viscometer,measured by setting the viscometer to spindle 62 and setting the spindlespeed to 60 rpm, or if the fluid in the beaker becomes optically clearwith no particles or insoluble matter visible to the human eye.

The degradation data after 1 day and 5 days is provided in Tables 1 and2.

TABLE 1 Test Data at maximum absorbency at day 1 Testing/Examples Daysto full degradation Sample SWF Lysozyme soln Hemcon gauze >30 days >30days CG 1600 chitosan >30 days >30 days Carboxymethylated chitosan >30days >30 days Chitosan/Viscose/Acid blend >30 days >30 days Celox(chitosan salt) >30 days >30 days Celox gauze >30 days >30 days Chitosangranules with 20% Acid >30 days >30 days Chitosan granules with 55% Acid  1 day   1 day

TABLE 2 Test Data at maximum absorbency at day 5 (gradually added fluidover 5 days) Testing/Examples Days to full degradation Sample SWFLysozyme soln Hemcon gauze >30 days >30 days CG 1600 chitosan >30days >30 days Carboxymethylated chitosan >30 days >30 daysChitosan/Viscose/Acid blend >30 days >30 days Celox (chitosan salt) >30days >30 days Celox gauze >30 days >30 days Chitosan granules with 20%Acid >30 days >30 days Chitosan granules with 55% Acid   5 day   5 day

It can therefore be seen that the haemostat compositions according tothe invention degrade effectively over a desired period of between 1 and30 days in conditions designed to replicate those that would beencountered in the human or animal body, and would be able to safelyremain in the human or animal body post-surgery to aid in reducing andpreventing incidences of re-bleeding and promoting healing, beforecompletely degrading and being excreted from the body naturally.

It is of course to be understood that the present invention is notintended to be restricted to the foregoing examples which are describedby way of example only.

The invention claimed is:
 1. A haemostat composition comprising achitosan, chitosan salt or chitosan derivative and a physiologicallyacceptable acid, wherein the physiologically acceptable acid is presentin an amount of between about 20% and about 70% by weight of thehaemostat composition, wherein the chitosan, chitosan salt or chitosanderivative is coated by the acid, wherein the haemostat composition isin a non-fibrous form, is able to fully degrade in a human or animalbody within about 30 days, and the chitosan, chitosan salt or chitosanderivative has been washed with an alkali solution prior to coating withthe acid for a period of longer than about 12 hours to reduce thepresence of endotoxins; wherein the alkali solution has a concentrationof 0.02 M to 0.2M.
 2. The haemostat composition according to claim 1,wherein the haemostat composition is in the form of granules, powder, asheet, a foam, a freeze dried foam, a compressed foam, a film, aperforated film, beads, a gel, a hydrogel sheets and amorphous hydrogel,or a laminate, or a combination of any two or more thereof.
 3. Thehaemostat composition according to claim 1, wherein the haemostatcomposition is still present in the human or animal body after about 24hours.
 4. The haemostat composition according to claim 3, whereincomplete degradation of the haemostat composition occurs after more thanabout 4 days but less than about 30 days.
 5. The haemostat compositionaccording to claim 4, wherein complete degradation of the haemostatcomposition occurs after more than about 7 days but less than about 30days.
 6. The haemostat composition according to claim 1, wherein thephysiologically acceptable acid is present in an amount of between about30% and about 60% by weight of the haemostat composition.
 7. Thehaemostat composition according to claim 6, wherein the physiologicallyacceptable acid is present in an amount of between about 35% and about55% by weight of the haemostat composition.
 8. The haemostat compositionaccording to claim 1, wherein the physiologically acceptable acidcomprises an organic acid and/or an inorganic acid.
 9. The haemostatcomposition according to claim 8, wherein the organic acid comprises acarboxylic acid.
 10. The haemostat composition according to claim 9,wherein the carboxylic acid is selected from formic acid, acetic acid,ascorbic acid, halogen acetic acids, propanoic acid, propenoic acid,lactic acid, succinic acid, acrylic acid, glyoxylic acid, pyruvic acidor a hydroxy propionic/butanoic acid, or combinations of any two or morethereof.
 11. The haemostat composition according to claim 10, whereinthe carboxylic acid is selected from lactic, acetic and succinic acids,or combinations of any two or more thereof.
 12. The haemostatcomposition according to claim 11, wherein the carboxylic acid is lacticacid.
 13. The haemostat composition according to claim 8, wherein theinorganic acid comprises one or more of hydrochloric acid and/orsulphuric acid.
 14. The haemostat composition according to claim 1,wherein the haemostat composition comprises a chitosan salt.
 15. Thehaemostat composition according to claim 14, wherein the chitosan saltcomprises one or more salts selected from chitosan acetate, chitosanlactate, chitosan succinate, chitosan malate, chitosan acrylate,chitosan formate, chitosan ascorbate, chitosan fluoroacetate, chitosanchloroacetate, chitosan propanoate, chitosan glyoxylate, chitosanpyruvate, chitosan sulphate, or chitosan chloride.
 16. The haemostatcomposition according to claim 15, wherein the chitosan salt compriseschitosan lactate.
 17. The haemostat composition according to claim 1,wherein the haemostat composition comprises a chitosan salt, thephysiologically acceptable acid is a carboxylic acid and is present inan amount of between about 45-60% by weight of the haemostatcomposition, and the haemostat composition is in the form of granules orpowder.
 18. The haemostat composition according to claim 1, wherein thehaemostat composition is made without subjecting the composition to anyheat treatment after the composition has been dried.
 19. The haemostatcomposition according to claim 1, wherein a molecular weight of thechitosan used for the preparation of the haemostat composition is lessthan about 500,000.
 20. The haemostat composition according to claim 1,wherein a viscosity of the chitosan used for the preparation of thehaemostat composition is from about 40 to about 200 cps when measured at20° C.
 21. The haemostat composition according to claim 1, wherein thehaemostat composition is sterilised.
 22. The haemostat compositionaccording to claim 1, further comprising one or more components selectedfrom pharmaceutical agents; wetting agents; colouring agents; processingaids; bulking agents; absorbent polymers; antimicrobial agents; growthfactors; cytokines; agents which absorb agents which delay healing;calcium; vitamin K; fibrinogen; thrombin; factor VII; factor VIII;clays; oxidised regenerated cellulose; gelatine; and/or collagen.
 23. Amethod of absorbing fluid discharged from a physiological target site,or of stemming a flow of a fluid discharged from a physiological targetsite, comprising applying to the physiological target site the haemostataccording to claim
 1. 24. The haemostat composition according to claim1, wherein the haemostat composition is sterilised prior to beingpackaged.
 25. The haemostat composition according to claim 1, whereinthe chitosan derivative is a reaction product of chitosan with one ormore compounds selected from the group consisting of carboxy methylchitosan, hydroxyl butyl chitin, N-acyl chitosan, O-acyl chitosan,N-alkyl chitosan, O-alkyl chitosan, N-alkylidene chitosan, O-sulfonylchitosan, sulfated chitosan, phosphorylated chitosan, nitrated chitosan,alkalichitin, alkalichitosan, and metal chelates.